New and improved treatments with novel mechanisms of action are needed for drug addiction, mood and anxiety disorders. The kappa opioid receptor (KOR) has recently been validated as a highly promising target for this purpose. Selective KOR antagonists may prevent stress-induced relapse, limit drug use, and provide antidepressant and anxiolytic effects. While available selective KOR antagonists (e.g., norBNI, JDTic) showed efficacy in rodent models used to study drug addiction, mood and anxiety disorders, they do not possess optimal properties to enter clinical studies. Specifically, a single dose in rodents or non-human primates induces long lasting (several weeks) in vivo KOR blockade after a slow onset of action (~24 h). Improved selective KOR antagonists are needed to determine if this class of compounds is effective in clinical settings. Recent efforts focusing on the design of drugs targeting the mu opioid receptor (MOR) have led to the identification of a small number of KOR antagonists with some degree of selectivity for KOR over MOR. These biaryl/diaryl ether containing compounds are structurally different from current KOR antagonists and have mostly been characterized in vitro. Preliminary observations indicate that these agents induce rapid KOR blockade (within 1 h post-administration). This distinguishes this class of compounds from all currently studied, prototypical KOR antagonists and strongly suggests that these compounds will possess a different, more drug-like, time course of KOR blockade. First, we propose to synthesize eleven biaryl/diaryl ether analogues: four known and seven newly designed agents. Binding and functional assays will then be used to assess in vitro KOR antagonist potency and selectivity for KOR over other opioid receptor subtypes. The standard KOR antagonists norBNI and JDTic will be tested under the same conditions to provide reference data. Finally, the two most potent and selective biaryl/diaryl ether agents and the standard KOR antagonist JDTic will be evaluated in the rat intracranial self stimulation test to provide information about in vivo potency and time course of KOR blockade. This assay is sensitive to the function of brain reward systems, making it specifically relevant to identifying agents that might have effects in drug addiction and mood disorders. The identification of short-acting KOR antagonists would have important implications. These agents could be used (1) as lead compounds for further chemical modification, if receptor selectivity needs to be increased, (2) in preclinical studies in which long-lasting KOR blockade is a limitation, and (3) for clinical studies in patients with drug addiction, depression and/or anxiety disorders. This work is of particular importance because it could lead to the development of clinically useful compounds with entirely new mechanisms of action for the treatment of drug addiction, mood and anxiety disorders. PUBLIC HEALTH RELEVANCE: Preclinical studies suggest that selective kappa opioid receptor antagonists have great potential to alleviate symptoms of drug addiction, mood and anxiety disorders. Using a combination of synthesis, in vitro, and in vivo evaluation, the proposed studies seek to identify a class of agents with optimal kappa opioid receptor antagonist properties for use in clinical trials. This work is of particular importance because it could lead to the development of clinically useful compounds with entirely new mechanisms of action, which might help those who respond poorly or inadequately to currently available treatments.